In 1996, DePodesta got his first baseball job with the Cleveland Indians, where he spent three seasons. He served as an advance scout for two years and, in his final month with the club, was appointed special assistant to General Manager John Hart.

DePodesta's reliance on sabermetric principles has been somewhat controversial. He is often considered part of a new breed of front-office executives whose personnel decisions depend heavily on analysis of performance data, often at the perceived expense of more traditional methods of scouting and observation.

One of DePodesta's most notable moves was made at the 2004 trading deadline. He traded catcher Paul Lo Duca, relief pitcher Guillermo Mota and outfielder Juan Encarnación to the Florida Marlins in exchange for pitcher Brad Penny, first baseman Hee Seop Choi and pitcher Bill Murphy, in what was reportedly an attempt to pick up pieces to acquire pitcher Randy Johnson from the Arizona Diamondbacks.[5] DePodesta was heavily criticized in the local and national baseball media for this trade, because Lo Duca was thought to be the "heart and soul" of the team. The Dodgers made the playoffs anyway, with Penny developing into one of the better pitchers in the National League during his stint with the Dodgers, which lasted until the end of the 2008 season. Hee Seop Choi, however, was a disappointment, batting just .161 in 2004 and .253 in 2005, and striking out 80 times in 320 at bats. Bill Murphy was traded that year to acquire Steve Finley, who hit 13 homers in 58 games, including a memorable grand slam that clinched the division title. Lo Duca played through 2005 with the Marlins and then went to the New York Mets, Washington Nationals and back to the Marlins, making his final Major League appearance in September 2008.

During the 2004 off-season, Adrián Beltré, who had hit 48 home runs in 2004, signed with Seattle as a free agent, spurning DePodesta's offer of 3 years for $30 million for Seattle's offer of 5 years for $64 million. DePodesta signed J. D. Drew, Jeff Kent, and Derek Lowe. Drew enjoyed two productive seasons as a Dodger and then used an opt-out clause in his contract to sign a new 5-year deal with the Boston Red Sox. Both Kent and Lowe put in four productive seasons for the Dodgers and cut ties with the franchise at the end of the 2008 season with Kent retiring and Lowe signing a contract with the Atlanta Braves.

Coming off the successes of 2004, the 2005 season saw the Dodgers lose a number of players to significant stints on the disabled list. Many of the players lost to injury were expected to produce heavily for the team including J. D. Drew, Milton Bradley, Éric Gagné, Jayson Werth, César Izturis and Odalis Pérez. The 2005 season resulted in the team's worst record since 1992 and second worst since moving to Los Angeles in 1958. On October 29, 2005, Dodgers owner Frank McCourt fired DePodesta, citing his desire to see the club win and that DePodesta had not met those expectations. Reports surfaced that the real reason McCourt had fired DePodesta was his inability to find satisfactory managerial candidates to replace Jim Tracy. He was later replaced by Ned Colletti, who hired Grady Little as manager. Some have speculated that McCourt fired DePodesta in response to media criticism from Los Angeles Times sports columnists T.J. Simers and Bill Plaschke, who were vehemently "anti-Moneyball" and referred to DePodesta pejoratively as "Google Boy," and is frequently referred to as "The Fifth Highwayman."

On June 30, 2006, DePodesta was hired as the Special Assistant for Baseball Operations for the San Diego Padres and was promoted to Executive Vice President on November 10, 2008.

On November 8, 2010, DePodesta was hired as the vice president of player development and scouting for the New York Mets by general manager Sandy Alderson, with whom DePodesta worked when Alderson was CEO of the Padres.[6]

Lewis's book examines the lives and careers of various baseball personalities and explains the art of sabermetrics. Bill James, who coined the term sabermetrics for the Society for American Baseball Research (SABR), is also a major focus.[10] James published "The Bill James Baseball Abstract" from 1977 to 1988 and wrote several sabermetrics books.[11] Beane and DePodesta had studied James's publications and were inspired by his knowledge of baseball analysis.[12]

DePodesta did not feel comfortable with being in the spotlight after the book's release,[13] nor did he care for the secrets revealed about his scouting methods.[14] The book earned DePodesta a reputation as a cold calculator and a man who always has his head in his computer, choosing players only on the criteria of numbers. In addition, he was thought of as a guy knowing nothing of "real baseball."

In reality, DePodesta played football in college and wanted to be a football coach,[13][15][16] seen in a photo wearing number 17.[17] After graduating from Harvard with a degree in economics, he became an intern for the Canadian Football League's Baltimore Stallions in 1995.[18] In early 1996, he got his first baseball job with the Cleveland Indians, where he worked as a scout. In October 1996, at the age of 24, he was promoted to the position of advanced scout. In October 1998, he became assistant to the General Manager for the team.[18] Those experiences led to him being hired by Beane as his assistant with the Oakland A's in November 1998.[16]

When the movie Moneyball was adapted from the book, DePodesta did not approve of the way that his character was being portrayed. "There were a handful of things. Some were factual, others were more ephemeral." He was clear it was nothing about Jonah Hill the actor playing his role. "Jonah was awesome. He was so respectful of me and my time. It would have been flattering to be portrayed by someone of his expertise. It had nothing to do with the casting," said DePodesta in 2010 to Yahoo Sports.[19] "I just could never get comfortable with the idea of somebody else portraying me to the rest of the world. Like any movie, to make it interesting, there has to be some conflict there. In some respects, a lot of the conflict is going to revolve around my character, and that was never really the case in reality," DePodesta told the Wall Street Journal.[20] He also talked about the caricatural focus it brought on him, first in 2003, then again in 2011. "The other problem was I wasn't all that interested in the attention. It had already happened from the book. And I didn't necessarily need to relive it."[13]

The role was originally going to be given DePodesta's name and portrayed by Demetri Martin. Since DePodesta did not want his name or likeness to be used in the movie, instead the character of "Peter Brand" was created. It is a composite of Beane's assistants [21] in Oakland, as the character is not an accurate representation of any specific real-life person.[22] However, Moneyball's director Bennett Miller has credited DePodesta for being generous and helpful in the making of the film. Brand was played by Jonah Hill, who was nominated for an Academy Award for Best Supporting Actor for his performance.

On December 13, 2012, DePodesta was elected to the Board of Directors of Sears Holdings Corporation. DePodesta has also served as a keynote speaker at numerous business conventions and has been recognized by several publications including Baseball Prospectus and Fortune Magazine, which named him as one of the Top 10 innovators under the age of 40.[23]

Note - Some teams may have both a President and CEO, in those cases the highest ranked of the two (according to the team), not counting the owner, is listed
(*) - de facto, has president/CEO powers but under a different title